PMID- 21602934
OWN - NLM
STAT- MEDLINE
DCOM- 20111021
LR  - 20240316
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 5
DP  - 2011
TI  - Excessive biologic response to IFNbeta is associated with poor treatment response in 
      patients with multiple sclerosis.
PG  - e19262
LID - 10.1371/journal.pone.0019262 [doi]
LID - e19262
AB  - BACKGROUND: Interferon-beta (IFNbeta) is used to inhibit disease activity in 
      multiple sclerosis (MS), but its mechanisms of action are incompletely 
      understood, individual treatment response varies, and biological markers 
      predicting response to treatment have yet to be identified. METHODS: The 
      relationship between the molecular response to IFNbeta and treatment response was 
      determined in 85 patients using a longitudinal design in which treatment effect 
      was categorized by brain magnetic resonance imaging as good (n = 70) or poor 
      response (n = 15). Molecular response was quantified using a customized cDNA 
      macroarray assay for 166 IFN-regulated genes (IRGs). RESULTS: The molecular 
      response to IFNbeta differed significantly between patients in the pattern and 
      number of regulated genes. The molecular response was strikingly stable for 
      individuals for as long as 24 months, however, suggesting an individual 'IFN 
      response fingerprint'. Unexpectedly, patients with poor response showed an 
      exaggerated molecular response. IRG induction ratios demonstrated an exaggerated 
      molecular response at both the first and 6-month IFNbeta injections. CONCLUSION: MS 
      patients exhibit individually unique but temporally stable biological responses 
      to IFNbeta. Poor treatment response is not explained by the duration of biological 
      effects or the specific genes induced. Rather, individuals with poor treatment 
      response have a generally exaggerated biological response to type 1 IFN 
      injections. We hypothesize that the molecular response to type I IFN identifies a 
      pathogenetically distinct subset of MS patients whose disease is driven in part 
      by innate immunity. The findings suggest a strategy for biologically based, 
      rational use of IFNbeta for individual MS patients.
FAU - Rudick, Richard A
AU  - Rudick RA
AD  - Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, 
      Cleveland, Ohio, United States of America. rudickr@ccf.org
FAU - Rani, M R Sandhya
AU  - Rani MR
FAU - Xu, Yaomin
AU  - Xu Y
FAU - Lee, Jar-Chi
AU  - Lee JC
FAU - Na, Jie
AU  - Na J
FAU - Shrock, Jennifer
AU  - Shrock J
FAU - Josyula, Anupama
AU  - Josyula A
FAU - Fisher, Elizabeth
AU  - Fisher E
FAU - Ransohoff, Richard M
AU  - Ransohoff RM
LA  - eng
GR  - P01 NS038667/NS/NINDS NIH HHS/United States
GR  - P50 NS038667/NS/NINDS NIH HHS/United States
GR  - UL1 RR024989/RR/NCRR NIH HHS/United States
GR  - P50NS38667/NS/NINDS NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110513
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 77238-31-4 (Interferon-beta)
SB  - IM
MH  - Adult
MH  - Brain/pathology
MH  - Female
MH  - Humans
MH  - Immunity, Innate
MH  - Interferon-beta/*pharmacology/therapeutic use
MH  - Longitudinal Studies
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Middle Aged
MH  - Multiple Sclerosis/*drug therapy/genetics
MH  - Oligonucleotide Array Sequence Analysis
MH  - Reproducibility of Results
MH  - Time Factors
MH  - Treatment Outcome
MH  - Up-Regulation/*drug effects/genetics
PMC - PMC3094352
COIS- Competing Interests: The authors have read the journal's policy and wish to 
      declare the following conflicts: All authors received support (paid to 
      institution) for this project via NIH-NINDS grant P50 NS 38667 (2004-2009), 
      Project 4 P01NS38667. [Rudick Richard] RMR was PI for the P50 and PO1; RAR was 
      director for Project 4. RAR: Consulting fees or honoraria: Biogen Idec, Novartis, 
      Teva [Rudick, Richard], Millennium [Rudick, Richard], Genzyme-Bayer [Rudick, 
      Richard],; Wyeth, Bayhill [Rudick, Richard], Pfizer Royalties: Informa Healthcare 
      Travel expenses paid: Novartis [Rudick, Richard], Millenium [Rudick, Richard], 
      Genzyme-Bayer [Rudick, Richard], Merck Serono [Rudick, Richard], Wyeth [Rudick, 
      Richard], Pfizer. RMR: Consultancies (within 12 mos): Abbott, Biogen, Johnson & 
      Johnson, Merck, Novartis, Pfizer, Teva Paid lectures (not speakers bureaus): 
      Biogen Idec, grand rounds only, not promotional Grants/grants pending (paid to 
      institution): NIH; NMSS; Biogen Idec; Chemocentryx EF: Consultancies: Biogen 
      Idec, Genzyme, Millenium, Pfizer, Wyeth Grants/grants pending (paid to 
      institution): Biogen, Genzyme, Millenium, Wyeth; NIH-NINDS. Honoraria: Biogen, 
      Teva Travel expenses: Biogen, Genzyme, Millenium, Wyeth, Pfizer. This does not 
      alter the authors' adherence to all the PLoS ONE policies on sharing data and 
      materials.
EDAT- 2011/05/24 06:00
MHDA- 2011/10/22 06:00
PMCR- 2011/05/13
CRDT- 2011/05/24 06:00
PHST- 2010/12/30 00:00 [received]
PHST- 2011/03/24 00:00 [accepted]
PHST- 2011/05/24 06:00 [entrez]
PHST- 2011/05/24 06:00 [pubmed]
PHST- 2011/10/22 06:00 [medline]
PHST- 2011/05/13 00:00 [pmc-release]
AID - PONE-D-11-00964 [pii]
AID - 10.1371/journal.pone.0019262 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(5):e19262. doi: 10.1371/journal.pone.0019262. Epub 2011 May 13.